Division of Clinical Outcome Assessment (DCOA), ODES, OND, CDER, US FDA
Rare Disease COA Consortium
t is estimated that more than 350 million people worldwide, approximately 10% of the global population, half of whom are children, live with a rare disease. Of these rare diseases, fewer than 10% have approved treatments. This significant unmet treatment need has been met with unprecedented response within the global scientific, biopharmaceutical, regulatory, and patient communities, including unprecedented growth in rare disease drug and gene therapy development and approvals. However, the well-known difficulties of conducting clinical trials (e.g., small samples, wide geographic distribution, heterogenous symptoms) and developing products for these rare indications persist, and identifying outcomes remains a hurdle. For efficacy endpoints based on clinical outcome assessments, COAs have not yet been identified, developed, or modified for most rare diseases.
The ongoing development of the Rare Disease COA Resource is a central pillar of the RD-COAC efforts and its mission to advance measurement for rare disease clinical trials. The RD-COAC Resource creates efficiencies for medical product development by freely providing all rare disease stakeholders with information on a published, curated COA library of drug development tools that may apply to a broad range of rare disease drug development programs. While a listing in the Rare Disease COA Resource is not an endorsement that a COA will meet regulatory evidence standards, it is an essential resource for streamlining the identification of COAs that matter to people living with rare diseases. By including COAs covering common concepts of interest across many rare diseases, the Rare Disease COA Resource may be used to identify COAs available to measure outcomes of interest in patient registries and natural history studies or in clinical development programs.
COAs included in the Rare Disease COA Resource represent the tools that are the most commonly used in current rare disease research and tools that have been published in the literature and were available to examine against evidentiary criteria. Therefore, the Rare Disease COA Resource only captures existing tools and may not include COAs that have been developed recently but currently lack publications to support their use. The Rare Disease COA Resource will be updated periodically to identify new tools that may warrant inclusion. The resource indicates the level of evidentiary standards and gaps for each COA included, to help guide users as to where there may be limitations to using a legacy COA. Additionally, some historical COAs have been included because, although they may not meet all evidentiary standards, they allow for comparisons between individual rare disease populations and normative data.
The methodology guiding the Rare Disease COA Resource included a subject matter expert committee of the RD-COAC comprising clinicians, academics including clinical researchers, and industry, National Institutes of Health (NIH), and FDA representatives who collaborated in the development process. The Rare Disease COA Resource development is an iterative, ongoing domain-specific development to expand the Rare Disease COA Resource based on voting member prioritization. A landscape analysis was conducted for COAs via a literature search from published clinical trials, professional meeting presentations, clinical practice guidelines, and natural history studies. This COA review and synthesis methods used were an adaptation of well-established systematic literature review methodology. Criteria were determined for the selection of COAs for an in-depth analysis of available measurement evidence (i.e., gap analysis). A second literature search was conducted to identify and retrieve available evidence for the selected COAs. A consensus process between each Advisory Panel and the Rare Disease COA Resource Development Subcommittee determined the final COAs to include in the Rare Disease COA Resource.
The inaugural domain for the Rare Disease COA Resource was “pediatric daily function,” comprising gross and fine motor functioning, self-care, and expressive and receptive communication. These domains were selected based on input from FDA, biopharmaceutical member firms, and patient advocates on what the highest priority domains were. Research is already underway for the next measurement topics of pain (e.g., pain severity, pain interference) and sleep (e.g., sleep disturbance, sleep impact), still in pediatric nononcologic populations.
The demonstrated success of the RD-COAC lies in its ability to bring scientific thought leaders together to enact change within the rare disease research field. The importance of incorporating the patient voice into rare disease clinical trials toward the development of meaningful outcomes necessitates continued collaboration from among patient advocates, regulatory bodies, academia, and government/industry sponsors. While the initial domains covered by the Rare Disease COA Resource focus on pediatric populations, the resource will be iteratively expanded to ultimately cover domains of interest across both pediatric and adult populations. These efforts will be important given the number of new treatment modalities (e.g., antisense oligonucleotides, immunology and gene therapies) which have the potential to alter the disease course and improve life expectancy and modify the background therapy of future clinical trials. The RD-COAC will continue to accelerate methodologic advances and address new opportunities for COA-based measurement to expedite solutions for emerging new treatment paradigms.